The DNA of eukaryotic cells is packaged into chromatin by winding of the DNA around histone proteins to form nucleosomes, the basic unit of chromatin. One of the important functions of chromatin is to determine regions of active and silenced transcription by changing the ordered chromatin structure. Such changes have profound effects on cellular function since they affect fundamental processes as differentiation, proliferation and apoptosis, and are often referred collectively to as “epigenetic” since they can lead to heritable changes that do not involve changes in gene sequences (Quina, A. S. et al. (2006), Biochem. Pharmacol. 72; 1563-1569)
These highly controlled chromatin changes are mediated by alterations histone proteins associated with DNA in the nucleosome. Most notably, the N-terminal histone tail of Histone H3 and histone H4 are subject to such covalent changes, which include changes in methylation, acetylation, phosphorylation and ubiquitination. The addition or removal of these groups on histones is mediated by specific enzymes, e.g., histone methyl transferases and histone demethylases for methyl groups, histone acetyltransferases and histone deacetylases for acetyl groups. In the event that the activity or expression of these “epigenetic” enzymes is not correctly controlled and regulated it may lead to disease. Cancer, in particular, is an area of high importance in relation to dysregulated epigenetic enzyme activity due to the role of epigenetics in cell differentiation, proliferation and apoptosis, but epigenetics may also play a role in other diseases such as metabolic, inflammatory, neurodegenerative and cardiovascular diseases. Therefore the selective modulation of aberrant action of epigenetic enzymes may hold great promise for the treatment of human disease (Kelly, T. K. et al. (2010), Nat. Biotechnol. 28; 1069-1078, and Cloos, P. et al. (2008), Genes. Dev. 22; 115-1140).
PCT/EP2013/070457 (WO2014/053491) discloses histone demethylase (HDME) inhibitors or activity modulators which are hereby incorporated by reference.
Embodiments of the application provide compounds capable of modulating the activity of histone demethylases and that are useful for the prevention and/or the treatment of diseases in which genomic disregulation is involved in the pathogenesis, e.g., cancer. By way of further example, malnutrition or poor nutrition is thought to have an adverse epigenetic effect and the compounds of the application may therefore have beneficial effect in treating such effects of poor nutrition. Furthermore, epigenetic changes have been found to be linked to behavior. Accordingly, compounds according to the application may be useful in behavior modification. Alternatively or additionally such compounds may be useful for exploring the extent to which different methylases are inhibited by similar compounds as an investigation of the structure, functionality and mechanism of action.